Database : MEDLINE
Search on : G02.111.720 [DeCS Category]
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  1 / 10810 MEDLINE  
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PMID:29355525
Author:Kim JL; Ha GH; Campo L; Breuer EK
Address:Department of Radiation Oncology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, 60153, USA.
Title:Negative regulation of BRCA1 by transforming acidic coiled-coil protein 3 (TACC3).
Source:Biochem Biophys Res Commun; 496(2):633-640, 2018 02 05.
ISSN:1090-2104
Country of publication:United States
Language:eng
Abstract:In spite of the push to identify modifiers of BRCAness, it still remains unclear how tumor suppressor BRCA1 is lost in breast cancers in the absence of genetic or epigenetic aberrations. Mounting evidence indicates that the transforming acidic coiled-coil 3 (TACC3) plays an important role in the centrosome-microtubule network during mitosis and gene expression, and that deregulation of TACC3 is associated with breast cancer. However, the molecular mechanisms by which TACC3 contributes to breast cancer development have yet to be elucidated. Herein, we found that high levels of TACC3 in human mammary epithelial cells can cause genomic instability possibly in part through destabilizing BRCA1. We also found that high levels of TACC3 inhibited the interaction between BRCA1 and BARD1, thus subsequently allowing the BARD1-uncoupled BRCA1 to be destabilized by ubiquitin-mediated proteosomal pathway. Moreover, there is an inverse correlation between TACC3 and BRCA1 expression in breast cancer tissues. Overall, our findings provide a new insight into the role of TACC3 in genomic instability and breast tumorigenesis.
Publication type:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
Name of substance:0 (BRCA1 Protein); 0 (Microtubule-Associated Proteins); 0 (TACC3 protein, human); 0 (Tumor Suppressor Proteins); EC 2.3.2.27 (BARD1 protein, human); EC 2.3.2.27 (Ubiquitin-Protein Ligases)


  2 / 10810 MEDLINE  
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PMID:28456689
Author:Mandic A; Strebinger D; Regali C; Phillips NE; Suter DM
Address:The Institute of Bioengineering (IBI), School of Life Sciences, Swiss Federal Institute of Technology Lausanne (EPFL), 1015 Lausanne, Switzerland.
Title:A novel method for quantitative measurements of gene expression in single living cells.
Source:Methods; 120:65-75, 2017 May 01.
ISSN:1095-9130
Country of publication:United States
Language:eng
Abstract:Gene expression is at the heart of virtually any biological process, and its deregulation is at the source of numerous pathological conditions. While impressive progress has been made in genome-wide measurements of mRNA and protein expression levels, it is still challenging to obtain highly quantitative measurements in single living cells. Here we describe a novel approach based on internal tagging of endogenous proteins with a reporter allowing luminescence and fluorescence time-lapse microscopy. Using luminescence microscopy, fluctuations of protein expression levels can be monitored in single living cells with high sensitivity and temporal resolution over extended time periods. The integrated protein decay reporter allows measuring protein degradation rates in the absence of protein synthesis inhibitors, and in combination with absolute protein levels allows determining absolute amounts of proteins synthesized over the cell cycle. Finally, the internal tag can be excised by inducible expression of Cre recombinase, which enables to estimate endogenous mRNA half-lives. Our method thus opens new avenues in quantitative analysis of gene expression in single living cells.
Publication type:JOURNAL ARTICLE
Name of substance:0 (Proteins); 0 (RNA, Messenger); EC 2.7.7.- (Cre recombinase); EC 2.7.7.- (Integrases)


  3 / 10810 MEDLINE  
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PMID:29194015
Author:Tripathi P; A JL; Kapoor M
Address:a Department of Protein Chemistry and Technology , CSIR-Central Food Technological Research Institute , Mysuru , Karnataka , India.
Title:Phytase from Citrobacter koseri PM-7: Enhanced production using statistical method and application in ameliorating mineral bioaccessibility and protein digestibility of high-phytate food.
Source:Prep Biochem Biotechnol; 48(1):84-91, 2018 Jan 02.
ISSN:1532-2297
Country of publication:England
Language:eng
Abstract:The present study was aimed at enhancing phytase (Phy-Ck) production from Citrobacter koseri PM-7 using response surface methodology (RSM) and improving the bioaccessibility of minerals (Fe and Zn) and protein digestibility in high-phytate food using Phy-Ck. A five-variable and three-level central composite design of RSM using wheat bran (6.681%, w/v), inoculum level (2.5%, v/v), and triton X-100 (0.2%, v/v) resulted in up to 5.57-fold (1.047 U/ml) improvement in Phy-Ck yield from C. koseri PM-7 when compared with fermentation media I and II. The model was successfully validated in the design space by taking a random set of variable combinations. Treatment of high-phytate food with partially purified Phy-Ck showed improvement in mineral bioaccessibility maximally for defatted sesame flour (DSF) (Fe 45.5%; Zn 50.7%) followed by wheat flour (WF) (Fe 13.5%; Zn 14.4%), green gram flour (GGF) (Fe 0.7%; Zn 3.8%) and defatted groundnut flour (DGF) (Zn 5.6%). The in vitro protein digestibility (IVPD) of WF increased from 48.83 to 65.04%, GGF from 45.04 to 57.12%, and DSF from 47.34 to 55.7% after Phy-Ck treatment.
Publication type:JOURNAL ARTICLE
Name of substance:0 (Dietary Fiber); 7IGF0S7R8I (Phytic Acid); E1UOL152H7 (Iron); EC 3.1.3.26 (6-Phytase); J41CSQ7QDS (Zinc)


  4 / 10810 MEDLINE  
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PMID:28457894
Author:Zupancic O; Bernkop-Schnürch A
Address:Department of Pharmaceutical Technology, Institute of Pharmacy, Leopold-Franzens-University Innsbruck, Innrain 80/82, Center for Chemistry and Biomedicine, 6020 Innsbruck, Austria.
Title:Lipophilic peptide character - What oral barriers fear the most.
Source:J Control Release; 255:242-257, 2017 Jun 10.
ISSN:1873-4995
Country of publication:Netherlands
Language:eng
Abstract:Peptide therapeutics is currently one of the fastest growing markets worldwide and consequently convenient ways of administration for these drugs are highly on demand. In particular, oral dosage forms would be preferred. A relative large molecular weight and high hydrophilicity, however, result in comparatively very low oral bioavailability being in most cases below 1%. Lipid based formulations (LBF), in particular self-emulsifying drug delivery systems (SEDDS) and solid lipid nanoparticles (SLN) as well as liposomes are among the most promising tools for oral peptide delivery. Key to success in orally delivering peptides via LBF seems to be a sufficiently high lipophilic character of those therapeutic agents. Hence, different non-covalent and covalent peptide lipidization methods from drug delivery point of view are presented. On the one hand, among non-covalent lipidization methods hydrophobic ion pairing seems to be a promising way to sufficiently increase peptide lipophilicity providing high drug payloads in the lipid phase, a protective effect against presystemic metabolism via thiol-disulphide exchange reactions and proteolysis as well as an improved intestinal membrane permeability. On the other hand, covalent methods like conjugating fatty acids via amidation, esterification, reversible aqueous lipidization (REAL) and cyclization also show potential. The present review therefore describes those lipidization methods in detail and critically evaluates their contribution in successfully overcoming the oral barriers.
Publication type:JOURNAL ARTICLE; REVIEW
Name of substance:0 (Lipids); 0 (Peptides); 0 (Vaccines)


  5 / 10810 MEDLINE  
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PMID:28463112
Author:Edens BM; Yan J; Miller N; Deng HX; Siddique T; Ma YC
Address:Department of Pediatrics, Northwestern University Feinberg School of Medicine, Ann & Robert H Lurie Children's Hospital of Chicago, Chicago, United States.
Title:A novel ALS-associated variant in regulates motor axon morphogenesis.
Source:Elife; 6, 2017 05 02.
ISSN:2050-084X
Country of publication:England
Language:eng
Abstract:The etiological underpinnings of amyotrophic lateral sclerosis (ALS) are complex and incompletely understood, although contributions to pathogenesis by regulators of proteolytic pathways have become increasingly apparent. Here, we present a novel variant in that is associated with ALS and show that its expression compromises motor axon morphogenesis in mouse motor neurons and in zebrafish. We further demonstrate that the ALS-associated variant impairs proteasomal function, and identify the Wnt signaling pathway effector beta-catenin as a substrate. Inhibition of beta-catenin function rescues the variant-induced motor axon phenotypes. These findings provide a strong link between the regulation of axonal morphogenesis and a new ALS-associated gene variant mediated by protein degradation pathways.
Publication type:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
Name of substance:0 (Carrier Proteins); 0 (Nuclear Proteins); 0 (UBQLN4 protein, human); 0 (beta Catenin); EC 3.4.25.1 (Proteasome Endopeptidase Complex)


  6 / 10810 MEDLINE  
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PMID:28460472
Author:Å Urga S; Nanut MP; Kos J; Sabotic J
Address:Department of Biotechnology, Jožef Stefan Institute, Ljubljana, Slovenia.
Title:Fungal lectin MpL enables entry of protein drugs into cancer cells and their subcellular targeting.
Source:Oncotarget; 8(16):26896-26910, 2017 Apr 18.
ISSN:1949-2553
Country of publication:United States
Language:eng
Abstract:Lectins have been recognized as promising carrier molecules for targeted drug delivery. They specifically bind carbohydrate moieties on cell membranes and trigger cell internalization. Fungal lectin MpL (Macrolepiota procera lectin) does not provoke cancer cell cytotoxicity but is able to bind aminopeptidase N (CD13) and integrin α3ß1, two glycoproteins that are overexpressed on the membrane of tumor cells. Upon binding, MpL is endocytosed in a clathrin-dependent manner and accumulates initially in the Golgi apparatus and, finally, in the lysosomes. For effective binding and internalization a functional binding site on the α-repeat is needed. To test the potential of MpL as a carrier for delivering protein drugs to cancer cells we constructed fusion proteins consisting of MpL and the cysteine peptidase inhibitors cystatin C and clitocypin. The fused proteins followed the same endocytic route as the unlinked MpL. Peptidase inhibitor-MpL fusions impaired both the intracellular degradation of extracellular matrix and the invasiveness of cancer cells. MpL is thus shown in vitro to be a lectin that can enable protein drugs to enter cancer cells, enhance their internalization and sort them to lysosomes and the Golgi apparatus.
Publication type:JOURNAL ARTICLE
Name of substance:0 (Collagen Type IV); 0 (Drug Carriers); 0 (Fungal Proteins); 0 (Glycoproteins); 0 (Lectins); 0 (Recombinant Fusion Proteins)


  7 / 10810 MEDLINE  
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PMID:28460458
Author:Fang Y; Wang J; Wang G; Zhou C; Wang P; Zhao S; Zhao S; Huang S; Su W; Jiang P; Chang A; Xiang R; Sun P
Address:Department of Immunology, School of Medicine, Nankai University, Tianjin, China.
Title:Inactivation of p38 MAPK contributes to stem cell-like properties of non-small cell lung cancer.
Source:Oncotarget; 8(16):26702-26717, 2017 Apr 18.
ISSN:1949-2553
Country of publication:United States
Language:eng
Abstract:Cancer stem cells (CSCs) are recognized as the major source for cancer initiation and recurrence. Yet, the mechanism by which the cancer stem cell properties are acquired and maintained in a cancer cell population is not well understood. In the current study, we observed that the level of active p38 MAPK is downregulated, while the level of the stemness marker SOX2 is upregulated in lung cancer tissues as compared to normal tissues. We further demonstrated that inactivation of p38 is a potential mechanism contributing to acquisition and maintenance of cancer stem cell properties in non-small cell lung cancer (NSCLC) cells. p38, in particular the p38γ and p38δ isoforms, suppresses the cancer stem cell properties and tumor initiating ability of NSCLC cells by promoting the ubiquitylation and degradation of stemness proteins such as SOX2, Oct4, Nanog, Klf4 and c-Myc, through MK2-mediated phosphorylation of Hsp27 that is an essential component of the proteasomal degradation machinery. In contrast, inactivation of p38 in lung cancer cells leads to upregulation of the stemness proteins, thus promoting the cancer stem cell properties of these cells. These findings have demonstrated a novel mechanism by which cancer stem cell properties are acquired and maintained in a cancer cell population, and have revealed a new function of the p38 pathway in suppressing cancer development. These studies have also identified a new pathway that can potentially serve as a target for cancer therapies aimed at eliminating CSCs.
Publication type:JOURNAL ARTICLE
Name of substance:0 (Biomarkers); 0 (SOX2 protein, human); 0 (SOXB1 Transcription Factors); EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases); EC 3.4.25.1 (Proteasome Endopeptidase Complex)


  8 / 10810 MEDLINE  
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PMID:28455345
Author:Wang D; Tosevska A; Heiß EH; Ladurner A; Mölzer C; Wallner M; Bulmer A; Wagner KH; Dirsch VM; Atanasov AG
Address:Department of Pharmacognosy, University of Vienna, Austria.
Title:Bilirubin Decreases Macrophage Cholesterol Efflux and ATP-Binding Cassette Transporter A1 Protein Expression.
Source:J Am Heart Assoc; 6(5), 2017 Apr 28.
ISSN:2047-9980
Country of publication:England
Language:eng
Abstract:BACKGROUND: Mild but chronically elevated circulating unconjugated bilirubin is associated with reduced total and low-density lipoprotein cholesterol concentration, which is associated with reduced cardiovascular disease risk. We aimed to investigate whether unconjugated bilirubin influences macrophage cholesterol efflux, as a potential mechanism for the altered circulating lipoprotein concentrations observed in hyperbilirubinemic individuals. METHODS AND RESULTS: Cholesterol efflux from THP-1 macrophages was assessed using plasma obtained from normo- and hyperbilirubinemic (Gilbert syndrome) humans (n=60 per group) or (heterozygote/homozygote Gunn) rats (n=20 per group) as an acceptor. Hyperbilirubinemic plasma from patients with Gilbert syndrome and Gunn rats induced significantly reduced cholesterol efflux compared with normobilirubinemic plasma. Unconjugated bilirubin (3-17.1 µmol/L) exogenously added to plasma- or apolipoprotein A1-supplemented media also decreased macrophage cholesterol efflux in a concentration- and time-dependent manner. We also showed reduced protein expression of the ATP-binding cassette transporter A1 (ABCA1), a transmembrane cholesterol transporter involved in apolipoprotein A1-mediated cholesterol efflux, in THP-1 macrophages treated with unconjugated bilirubin and in peripheral blood mononuclear cells obtained from hyperbilirubinemic individuals. Furthermore, we demonstrated that bilirubin accelerates the degradation rate of the ABCA1 protein in THP-1 macrophages. CONCLUSIONS: Cholesterol efflux from THP-1 macrophages is decreased in the presence of plasma obtained from humans and rats with mild hyperbilirubinemia. A direct effect of unconjugated bilirubin on cholesterol efflux was demonstrated and is associated with decreased ABCA1 protein expression. These data improve our knowledge concerning bilirubin's impact on cholesterol transport and represent an important advancement in our understanding of bilirubin's role in cardiovascular disease.
Publication type:JOURNAL ARTICLE
Name of substance:0 (ABCA1 protein, human); 0 (APOA1 protein, human); 0 (ATP Binding Cassette Transporter 1); 0 (Apolipoprotein A-I); 97C5T2UQ7J (Cholesterol); RFM9X3LJ49 (Bilirubin)


  9 / 10810 MEDLINE  
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PMID:28744580
Author:Wester A; Devocelle M; Tallant EA; Chappell MC; Gallagher PE; Paradisi F
Address:School of Chemistry, University College Dublin, Dublin, Ireland.
Title:Stabilization of Angiotensin-(1-7) by key substitution with a cyclic non-natural amino acid.
Source:Amino Acids; 49(10):1733-1742, 2017 10.
ISSN:1438-2199
Country of publication:Austria
Language:eng
Abstract:Angiotensin-(1-7) [Ang-(1-7)], a heptapeptide hormone of the renin-angiotensin-aldosterone system, is a promising candidate as a treatment for cancer that reflects its anti-proliferative and anti-angiogenic properties. However, the peptide's therapeutic potential is limited by the short half-life and low bioavailability resulting from rapid enzymatic metabolism by peptidases including angiotensin-converting enzyme (ACE) and dipeptidyl peptidase 3 (DPP 3). We report the facile assembly of three novel Ang-(1-7) analogues by solid-phase peptide synthesis which incorporates the cyclic non-natural δ-amino acid ACCA. The analogues containing the ACCA substitution at the site of ACE cleavage exhibit complete resistance to human ACE, while substitution at the DDP 3 cleavage site provided stability against DPP 3 hydrolysis. Furthermore, the analogues retain the anti-proliferative properties of Ang-(1-7) against the 4T1 and HT-1080 cancer cell lines. These results suggest that ACCA-substituted Ang-(1-7) analogues which show resistance against proteolytic degradation by peptidases known to hydrolyze the native heptapeptide may be novel therapeutics in the treatment of cancer.
Publication type:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
Name of substance:0 (Peptide Fragments); 9041-90-1 (Angiotensin I); EC 3.4.14.- (Dipeptidyl-Peptidases and Tripeptidyl-Peptidases); EC 3.4.14.4 (DPP3 protein, human); EC 3.4.15.1 (Peptidyl-Dipeptidase A); IJ3FUK8MOF (angiotensin I (1-7))


  10 / 10810 MEDLINE  
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PMID:29329072
Author:De Prins A; Martin C; Van Wanseele Y; Skov LJ; Tömböly C; Tourwé D; Caveliers V; Van Eeckhaut A; Holst B; Rosenkilde MM; Smolders I; Ballet S
Address:Research Group of Organic Chemistry, Departments of Chemistry and Bioengineering Sciences, Vrije Universiteit Brussel, Pleinlaan 2, 1050, Brussels, Belgium; Department of Pharmaceutical Chemistry, Drug Analysis and Drug Information, Center for Neurosciences (C4N), Vrije Universiteit Brussel, Laarbee
Title:Development of potent and proteolytically stable human neuromedin U receptor agonists.
Source:Eur J Med Chem; 144:887-897, 2018 Jan 20.
ISSN:1768-3254
Country of publication:France
Language:eng
Abstract:Neuromedin U (NMU) is a highly conserved endogenous peptide that is involved in a wide range of physiological processes such as regulation of feeding behavior, the stress response and nociception. The major limitation to use NMU as a therapeutic is its short half-life. Here, we describe the development of a set of novel NMU-analogs based on NMU-8, by introducing unnatural amino acids into the native sequence. This approach shows that it is possible to generate molecules with increased potency and improved plasma stability without major changes of the peptidic nature or the introduction of large conjugates. When compared to the native NMU-8 peptide, compounds 16, 18 and 20 have potent agonist activity and affinity for both NMU receptors. Selectivity towards NMUR1 was observed when the Phe residue in position 4 was modified, whereas higher potencies at NMUR2 were found when substitutions of the Pro residue in position 6 were executed. To study the effect of the modifications on the proteolytic stability of the molecules, an in vitro stability assay in human plasma at 37 °C was performed. All analyzed analogs possessed an increased resistance against enzymatic degradation in human plasma resulting in half-lifes from 4 min for NMU-8, up to more than 23 h for compound 42.
Publication type:JOURNAL ARTICLE
Name of substance:0 (Neuropeptides); 0 (Receptors, Neurotransmitter); 0 (neuromedin U receptor); 98530-27-9 (neuromedin U 8)



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